Endosomal recycling disorders: a novel disease entity caused by endosomal recycling defects

• Project/Area Number: 20K21583
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Nagoya City University
• Principal Investigator: Saitoh Shinji 名古屋市立大学, 医薬学総合研究院(医学), 教授 (00281824)
• Co-Investigator(Kenkyū-buntansha): 大石 久史 名古屋市立大学, 医薬学総合研究院(医学), 教授 (30375513)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: エンドソームリサイクル / 膜蛋白 / retriever / retromer / VPS35L / MAGEL2 / エンドソーム

Outline of Research at the Start

本研究では3C/ RSS様症状を示す患者およびretromer複合体関連疾患であるMAGEL2遺伝子変異が原因のSchaaf-Yang症候群患者を集積し臨床症状の比較検討を行い、データベースを作成する。さらに、細胞への遺伝子導入や遺伝子改変によりretromerおよびretriever複合体間のクロストークを解明する。そして、VPS35LおよびMAGEL2遺伝子改変マウスの発生段階に応じた脳の解析を行い、エンドソームリサイクル関連遺伝子の発生的変化を解明し、エンドソームリサイクル病としての新しい疾患概念を確立する。

Outline of Final Research Achievements

We have identified three new cases of VPS35L-related Ritscher-Schinzel syndrome (RSS), one Japanese, one French, and one Dutch case, and delineated clinical features. This is the largest collection of patients with VPS35L-related RSS, and now we have established the new clinical entity of VPS35L-related RSS. Regarding Schaaf-Yang syndrome (SYS), we have collected detailed clinical information from 25 Japanese patients with genetically confirmed SYS.
We also successfully established tissue specific conditional knock-out mice (central nervous system and mesenchymal stem cell), and recapitulate clinical features of VPS35L-related RSS. Using the mouse models, we successfully identified altered expression of membrane integral proteins.

Academic Significance and Societal Importance of the Research Achievements

膜蛋白のリサイクルに必須な分子機構であるエンドソームリサイクルを担うretromerおよびretriever複合体の機能障害により先天性疾患が発症することを明らかにし、エンドソームリサイクル病の疾患概念を提唱した。新しい生物学的機構の障害による疾患の存在を明らかにしたことで、エンドソームリサイクルに注目した病態解明および治療法開発のパラダイムが広がることが期待される。さらに、モデル動物を作成したことで、疾患研究の基盤を作ることができた。

Research Products

• [Journal Article] Hemorrhagic shock and encephalopathy syndrome in a patient with a de novo heterozygous variant in KIF1A (2022)
  • Author(s): Isobe Kouji、Ieda Daisuke、Miya Fuyuki、Miyachi Rieko、Otsuji Shiomi、Asai Masami、Tsunoda Tatsuhiko、Kosaki Kenjiro、Hattori Ayako、Saitoh Shinji、Mizuno Mihoko
  • Journal Title: Brain and Development Volume: 44 Issue: 3 Pages: 249-253
  • DOI: 10.1016/j.braindev.2021.11.007
  • Peer Reviewed
• [Journal Article] <i>Itpr1</i> regulates the formation of anterior eye segment tissues derived from neural crest cells (2021)
  • Author(s): Kinoshita Akira、Ohyama Kaname、Tanimura Susumu、Matsuda Katsuya、Kishino Tatsuya、Negishi Yutaka、Asahina Naoko、Shiraishi Hideaki、Hosoki Kana、Tomiwa Kiyotaka、Ishihara Naoko、Mishima Hiroyuki、Mori Ryoichi、Nakashima Masahiro、Saitoh Shinji、Yoshiura Koh-ichiro
  • Journal Title: Development Volume: 148 Issue: 16 Pages: 188755-188755
  • DOI: 10.1242/dev.188755
  • Peer Reviewed / Open Access
• [Journal Article] Utility of breakpoint‐specific nested polymerase chain reaction for the diagnosis of Emanuel syndrome (2021)
  • Author(s): Hayakawa Kozue、Kawase Koya、Fujimoto Masanori、Nakamura Yuji、Saitoh Shinji
  • Journal Title: Pediatrics International Volume: 63 Issue: 12 Pages: 1534-1536
  • DOI: 10.1111/ped.14644
  • Peer Reviewed
• [Journal Article] A case of ATR-X syndrome with mitochondrial respiratory chain dysfunction (2021)
  • Author(s): Aiba Kaori、Nakamura Yuji、Sugimoto Mari、Yatsuka Yukiko、Okazaki Yasushi、Murayama Kei、Ohtake Akira、Yokochi Kenji、Saitoh Shinji
  • Journal Title: European Journal of Medical Genetics Volume: 64 Issue: 8 Pages: 104251-104251
  • DOI: 10.1016/j.ejmg.2021.104251
  • Peer Reviewed
• [Journal Article] Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant (2021)
  • Author(s): Hori Ikumi、Ieda Daisuke、Ito Shogo、Ebe Seimi、Nakamura Yuji、Ohashi Kei、Aoyama Kohei、Hattori Ayako、Kokubo Minoru、Saitoh Shinji
  • Journal Title: Brain and Development Volume: 43 Issue: 4 Pages: 590-595
  • DOI: 10.1016/j.braindev.2020.12.008
  • Peer Reviewed / Open Access
• [Journal Article] A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders (2021)
  • Author(s): Kato Kohji、Miya Fuyuki、Oka Yasuyoshi、Mizuno Seiji、Saitoh Shinji
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 5 Pages: 491-498
  • DOI: 10.1038/s10038-020-00868-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Homozygous ADCY5 mutation causes early-onset movement disorder with severe intellectual disability (2021)
  • Author(s): Okamoto Nobuhiko、Miya Fuyuki、Kitai Yukihiro、Tsunoda Tatsuhiko、Kato Mitsuhiro、Saitoh Shinji、Kanemura Yonehiro、Kosaki Kenjiro
  • Journal Title: Neurological Sciences Volume: - Pages: 2975-2978
  • DOI: 10.1007/s10072-021-05152-y
  • Peer Reviewed
• [Journal Article] Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect (2021)
  • Author(s): Yamamoto Hidenori、Hayano Satoshi、Okuno Yusuke、Onoda Atsuto、Kato Kohji、Nagai Noriko、Fukasawa Yoshie、Saitoh Shinji、Takahashi Yoshiyuki、Kato Taichi
  • Journal Title: International Journal of Cardiology Volume: 326 Pages: 81-87
  • DOI: 10.1016/j.ijcard.2020.10.032
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex. (2020)
  • Author(s): Kato K, Okuno Y, Vasilev FF, Otomo T, Oishi H, Muramatsu H, Kawano Y, Oka Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S.
  • Journal Title: Journal of Medical genetics Volume: 57 Issue: 4 Pages: 245-253
  • DOI: 10.1136/jmedgenet-2019-106213
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes (2020)
  • Author(s): Ieda Daisuke、Negishi Yutaka、Miyamoto Tomomi、Johmura Yoshikazu、Kumamoto Natsuko、Kato Kohji、Miyoshi Ichiro、Nakanishi Makoto、Ugawa Shinya、Oishi Hisashi、Saitoh Shinji
  • Journal Title: PLOS ONE Volume: 15 Issue: 8 Pages: e0237814-e0237814
  • DOI: 10.1371/journal.pone.0237814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Scinzel-like syndrome: Description of two novel cases confirming the pathogenicity and clinical diversity. (2021)
  • Author(s): Otsuji S, Kato K, Lequesne CH, Mizuno S, Rio M, Miyatake S, Nishio Y, Matsumoto N, Cormier-Daire V, Saitoh S
  • Organizer: American Society of Human Genetics Virtual Meeting 2021
  • Int'l Joint Research
• [Presentation] ミトコンドリアホスホリパーゼPNPLA8機能喪失は神経系細胞においてミトコンドリアダイナミクス異 常を引き起こす. (2021)
  • Author(s): 中村勇治、嶋田逸誠、加藤洋一、齋藤伸治
  • Organizer: 第66回日本人類遺伝学会
• [Presentation] NAA15遺伝子の変異に伴う重度知的発達症ならびに自閉スペクトラム症の男児の一例. (2021)
  • Author(s): 大橋圭、川岡奈緒実、谷合弘子、三宅紀子、松本直通、齋藤伸治
  • Organizer: 第63回日本小児神経学会学術集会
• [Presentation] Mild Phenotypic features associated with non-truncating UBE3A mutations in Angelman syndrome. (2020)
  • Author(s): Yuji Nakamura, Kana Hosoki, Daisuke Ieda, Ikumi Hori, Yutaka Negishi, Ayako Hattori, Shinji Saitoh
  • Organizer: 第62回日本小児神経学会学術集会
• [Presentation] 当院でエキソーム解析を実施した小児神経疾患症例の臨床的検討 (2020)
  • Author(s): 堀いくみ, 宮冬樹, 中島光子, 中村勇治, 家田大輔, 大橋圭, 根岸豊, 服部文子, 安藤直樹, 角田達彦, 才津浩智, 金村米博, 小崎健次郎, 齋藤伸治
  • Organizer: 第62回日本小児神経学会学術集会
• [Presentation] A novel case with biallelic VPS35L variants confirms VPS35L as a causative gene of 3C/Ritscher-Schinzel-like syndrome. (2020)
  • Author(s): Shiomi Otsuji, Kohji Kato, Seiji Mizuno, Satoko Miyatake, Naomichi Matsumoto, Shinji Saitoh
  • Organizer: 第65回人類遺伝学会